Title : Novel insights into eukaryotic γ
-glutamyltranspeptidase 1 from the crystal structure of the glutamate-bound human
enzyme
Abstract :
- The enzyme γ -glutamyltranspeptidase 1 ( GGT1 ) is a conserved member of the N-terminal nucleophile hydrolase family that cleaves the γ-glutamyl bond of glutathione and other γ-glutamyl compounds
- In animals, GGT1 is expressed on the surface of the cell and has critical roles in maintaining cysteine levels in the body and regulating intracellular redox status
- Expression of GGT1 has been implicated as a potentiator of asthma, cardiovascular disease, and cancer
- The rational design of effective inhibitors of human GGT1 ( hGGT1 ) has been delayed by the lack of a reliable structural model
- The available crystal structures of several bacterial GGTs have been of limited use due to differences in the catalytic behavior of bacterial and mammalian GGTs
- We report the high resolution (1.67 Å) crystal structure of glutamate-bound hGGT1 , the first of any eukaryotic GGT
- Comparisons of the active site architecture of hGGT1 with those of its bacterial orthologs highlight key differences in the residues responsible for substrate binding, including a bimodal switch in the orientation of the catalytic nucleophile ( Thr-381 ) that is unique to the human enzyme
- Compared with several bacterial counterparts, the lid loop in the crystal structure of hGGT1 adopts an open conformation that allows greater access to the active site
- The hGGT1 structure also revealed tightly bound chlorides near the catalytic residue that may contribute to catalytic activity
- These are absent in the bacterial GGTs
- These differences between bacterial and mammalian GGTs and the new structural data will accelerate the development of new therapies for GGT1-dependent diseases